Tuesday, April 2, 2013

CTGF(CCN2), height increase target gene

CCN2 could increase adult height by accelerating the rate of endochondral ossification but keeping the epiphyseal growth plate the same size resulting in more growth. CCN2 is also associated with the height gene IGF2.

CTGF meets the criteria for a height growth target where overexpression increases height and underexpression decreases height. However this was only for cartilage specific expression of CTGF. Overexpression of CTGF has been found to have catabolic effects on muscle.

Glucosamine and CLA are potential ways to increase CTGF levels however can a global increase of CTGF increase height like a cartilage specific one? Does anyone know any other supplements that can increase CTGF? Prefereably only in the cartilage.

It should be noted that CTGF is only a promising target for people with open growth plates.

"CCN family member 2/connective tissue growth factor (CCN2) promotes the proliferation, differentiation, and maturation of growth cartilage cells in vitro. We generated transgenic mice overexpressing CCN2 and analyzed them with respect to cartilage and bone development. Transgenic mice were generated expressing a ccn2/lacZ fusion gene in cartilage under the control of the 6 kb-Col2a1-enhancer/promoter. Changes in cartilage and bone development were analyzed. Primary chondrocytes as well as limb bud mesenchymal cells were cultured and analyzed for changes in expression of cartilage–related genes, and non-transgenic chondrocytes were treated in culture with recombinant CCN2. Newborn transgenic mice showed extended length of their long bones, increased content of proteoglycans and collagen II accumulation. Transgenic bones indicated increases in bone thickness and mineral density. Chondrocyte proliferation was enhanced in the transgenic cartilage. In in vitro short-term cultures of transgenic chondrocytes, the expression of col2a1, aggrecan and ccn2 genes was substantially enhanced; and in long-term cultures the expression levels of these genes were further enhanced. Also, in vitro chondrogenesis was strongly enhanced. IGF-I and IGF-II mRNA levels were elevated in transgenic chondrocytes, and treatment of non-transgenic chondrocytes with recombinant CCN2 stimulated the expression of these mRNA. The addition of CCN2 to non-transgenic chondrocytes induced the phosphorylation of IGFR, and ccn2-overexpressing chondrocytes showed enhanced phosphorylation of IGFR. The observed effects of CCN2 may be mediated in part by CCN2-induced overexpression of IGF-I and IGF-II. CCN2-overexpression in transgenic mice accelerated the endochondral ossification processes, resulting in increased length of their long bones."

" At 8 weeks, the majority of the transgenic mice were about 12% larger than their wild-type littermates"

"Safranin-O staining indicated consistently an enhanced density of proteoglycans in the transgenic cartilage in comparison with cartilage of wt littermates"

" the enhanced matrix deposition did not result in an increase in the size of the cartilaginous epiphysis; rather, the extended bone length was the result of an elongated bony shaft of the diaphysis."

"Staining of the skeleton of transgenic embryos with type X collagen antibodies indicated that the hypertrophic zone was shorter in the transgenic embryos than in their wt littermates"<-So does CTGF Col2a1 specific overexpression increase adult height or just accelerate growth rate?

"Chondrogenic differentiation of limb-bud mesenchymal cells from CCN2 transgenic animals was greatly enhanced as compared with that of their wild-type counterparts"<-this could result in increased adult height.

According to Oral glucosamine increases expression of transforming growth factor β1 (TGFβ1) and connective tissue growth factor (CTGF) mRNA in rat cartilage and kidney: implications for human efficacy and toxicity., glucosamine increases CTGF in cartilage. The increase in CTGF was in articular but not growth cartilage. It wasn't huge but it was a significant increase 2.3-fold.

CCN2/CTGF is required for matrix organization and to protect growth plate chondrocytes from cellular stress.
"The loss of CCN2 leads to perinatal lethality resulting from a severe chondrodysplasia. Upon closer inspection of Ccn2 mutant mice, we observed defects in extracellular matrix (ECM) organization and hypothesized that the severe chondrodysplasia caused by loss of CCN2 might be associated with defective chondrocyte survival. Ccn2 mutant growth plate chondrocytes exhibited enlarged endoplasmic reticula (ER), suggesting cellular stress. Immunofluorescence analysis confirmed elevated stress in Ccn2 mutants, with reduced stress observed in Ccn2 overexpressing transgenic mice. In vitro studies revealed that Ccn2 is a stress responsive gene in chondrocytes. The elevated stress observed in Ccn2-/- chondrocytes is direct and mediated in part through integrin α5. The expression of the survival marker NFκB and components of the autophagy pathway were decreased in Ccn2 mutant growth plates, suggesting that CCN2 may be involved in mediating chondrocyte survival. Absence of a matricellular protein can result in increased cellular stress and highlight a novel protective role for CCN2 in chondrocyte survival. The severe chondrodysplasia caused by the loss of CCN2 may be due to increased chondrocyte stress and defective activation of autophagy pathways, leading to decreased cellular survival. These effects may be mediated through nuclear factor κB (NFκB) as part of a CCN2/integrin/NFκB signaling cascade."

"ER enlargement is a hallmark of defective protein folding and cellular stress. ER and other forms of cellular stress activate the Unfolded Protein Response (UPR), an adaptive mechanism to restore cell homeostasis and viability"

In this study CCN2 overexpression did not seem to result in increased height in rats. But the structure of the skeletons is different. The growth plate height in CCN2 mice was lower. The scientists did mention progressive overgrowth of cartilage elements.

" CCN2 promotes the proliferation and differentiation of growth-plate chondrocytes"

" the over-expression of CCN2 in cartilage stimulated the proliferation and differentiation of growth-plate chondrocytes, resulting in the promotion of endochondral ossification."

Expression of CCN2 can be induced by TGF-Beta.

In this study mice overexpressing CCN2 had longer bones on postnatal day 1.

" In in vitro short-term cultures of chondrocytes prepared from the cartilage of ccn2-over-expressing mice, the expression of col2a1, aggrecan and ccn2 was substantially enhanced; and in long-term cultures the expression levels of these genes were further enhanced"

"IGF-I and IGF-II mRNA levels were elevated in the transgenic chondrocytes, and treatment of non-transgenic chondrocytes with CCN2 stimulated the expression of these mRNAs"